1-oxyalkyl-4-hydroxyalkyl-4-phenyl piperidines



United States Patent M 3,108,111 I-OXYALKYL-4-HYDROXYALKYL-4-PHENYLPIPERKDINES Edward Sever-in Stern, Robert Lawson Watt, and DenisGeoffrey Hardy, all of Edinburgh, Scotland, assignors to J. F. MacFarlan& Company Limited, Boreham Wood, England, a British company No Drawing.Filed July 1, 1959, Ser. No. 824,181 Claims priority, application GreatBritain July 14, 1958 5 Claims. (Cl. 260-2947) This invention relates tonovel piperidine compounds and their production.

The compounds of the present invention are of the general formula:

N-alk-R Y where X is a phenyl group, Y is a hy droxymethyl (CH OH),hydroxyethyl, or hydroxypropyl group, alk is an alkylene group (straightor 'branchchain) containing up to six carbon atoms, and R is:

(a) an alk-oxy group containing up to six carbon atoms, or

(11) an aryloxy group, or

(c) an aralkoxy group, or

(d) a group containing a heterocyclic oxygen atom,

(e) an aryl group, or

(f) a heterocyclic residue carrying a basic nitrogen atom (e.g.pyridine, piperidine, morpholine, piperazine), or

(g) an alkoxy group carrying'a further oxygenated substituent 'such as ahydroxy, ethoxy or phenoxy group.

The substances of the present invention are new; they have valuableproperties, in particular cough-suppressant potency Withoutpethidine-like analgesic properties. The analgesic action exhibited bysome of the substances is mild and the substances are non-addictive.

The inter-mediates 4-hydroxymethyl-4-phenylpiperidine and4-1'=hydroxypropyl-4-phenylpiperidine hereinafter described are also newsubstances.

The present invention also includes processes for the preparation of thenovel compounds of the present invention. Thus, the compounds may beprepared by reduction (catalytic or chemical) of compounds of thegeneral formula:

N allcR Y where X, alk and R are as defined above and Y is either acarbomethoxy, carbethoxy or propoxycarbonyl group, or an acetyl orpropionyl group. Thus, the primary alcohol group may be introduced intothe otherwise preformed molecule and it may subsequently be alkylated oracylated as desired. Alternatively, the secondary base where X and Y areas defined above may be alkyla-ted with a halide R--a lkCl, R--alk--Br,or Ra1k--I, Where R and alk are as defined above.

3,103,:1 l l Patented Oct. 22, 1963 The following examples, in whichparts are by Weight, illustrate the invention:

EXAMPLE 1 4-H ydr0xymethyl-4-Phenyl-1-Tetrahydrofurfuryloxyethylpiperidine Ethyl4-phenyl-l-tetrahydrofurturyloxyethylpiperidine- 4 carb0xylate (8 parts)was dissolved in dry other parts) and added to lithium aluminium hydride(1 part) in dry ether (120 parts). The resulting suspension was boiledfor 10 minutes and then cooled and treated with a 20% aqueous solution(75 parts) of Rochelle salt. After ether extraction and evaporation ofthe other the oily residue was distilled. 111: had B.P. 160 C./0.05 mrn.and crystallised on standing. Its refractive index, 11 was 1.5303.

EXAMPLE 2 EXAMPLE 3 4 -Hydr0xymelhy l-4 -Ph enyl-l-4'-Ethoxybutylpiperidine Ethyl4-phenyl-1-4-ethoxybutylpiperidine-4-carboxylate (10 parts) wasdissolved in dry ether and added to a 1% ethereal solution parts) oflithium aluminium hydride. After boiling for 10 minutes the solution wasdecomposed with dilute aqueous hydrochloric acid and ether extracted.Distillation of the dried organic phase gave4-hydroxymethy1-4phenyl-1-4'-ethoxybutyl piperidine, B.P. C./O.4 mm, 211.5180.

EXAMPLE 4 4-Hydr0xymethyl-4-Phenyl-1-2'-Ethoxyethylpiperidine Ethyl4-phenyl-1-2'-ethoxyethylpiperidine-4-carboxylate (10 parts) wasdissolved in alcohol (35 parts) and sodium (5 parts) was added. When thevigorous reaction had subsided more sodium (5 parts) was added and thesolution was boiled for 30 minutes. The solution was then cooled,diluted with ten volumes of water, and exhaustively extracted withether. Distillation of the dried ethereal extracts gave4-hydroxymethyl-4-phenyl-l-2-ethoxyethylpiperidine, B.P. 146-150 C., 111.5240, which solidified on keeping and on crystallisation from ethylacetate-light petroleum mixture had M.P. l03104 C.

EXAMPLE 5 4-1 '-Hydroxypropyl-4-Phenyl-1-2-Phen0xyethylpiperidine Ethyl4-phenyl-4-propionyl-1-2-phenoxyethylpiperidine was hydrogenated inethanol over Adams catalyst. Atter absorption of 1 equivalent ofhydrogen, the reaction ceased and the reaction mixture was filtered.Evaporation of the "alcohol and addition of concentrated aqueous hydro-=bromic acid gave 4-1-hydroxypropyl-4-phenyl-1-2'-phenoxyethylpiperidinein form of its crystalline hydrobromide, M.P. 178 C.

EXAMPLE 6 4 -Hydroxymethyl-1 -Phenelhyl-4-Phenylpiperidine Reduction ofethyl 4-phenylpiperidine-4-c arboxylate (20 parts) with lithiumaluminium hydride (1.5 parts) in ether afforded4-11ydroxymethyl-4-phenylpiperidine (15 pants), M.P. 80 C. Thissecondary base (10 parts) was treated with phenethyl chloride (10 parts)and sodium carbonate (2 parts) in boiling amyl alcohol for 48 hours.Filtration and evaporation then gave4-hydroxymethyl-lphenethyl-4-phenylpiperidiue which crystallised onkeeping and had M.P. 108 C.

EXAMPLE 7 4-Hydroxymethyl- -Phenyl-1-Tetrahydr0furfurylpiperidine Ethyl4-phenyl-1 tetrahyd-rofurfurylpiperidine 4 oarboxylate (10 parts) wasdissolved in ether and added slowly to a 1% ethereal solution (125parts) of lithium aluminium hydride. The suspension was stirred andboiled for 10 minutes, and then treated with aqueous Rochelle salt.Exhaustive ether extraction and distillation gave 4-hydroxymethyl-4-phenyl 1 tetrahydrofurturylpiperidine, B.P. 180 C./0.3mm, 11 1.5480, which solidified on keeping and had M.P. 7880 C.

EXAMPLE 8 4-H ydroxymethyl-4-Phenyl-Z -2-M0rph0li0netlzyl pipev'ia'ineEthyl 4aphenyl-l-2'-morpholinoethylpiperidine 4 carboxylate was reducedby the method of Example 7. The base, 4-hyd roxymethyl-4-phenyl 1 2morpholinoethylpiperidine, obtained had M.P. 130 C.

EXAMPLE 9 4 -H yd roxymethyl-4-Ph enyl-I -2'-Piperidin0ethylpiperidineReduction, by the method detailed in Example 7, of ethyl4-phenyl-1-2'-piperidinoethylpiperidine-4-carboxylate gave4-hydroxymethyl-4-phenyl-l-2'-piperidinoethylpiperidine, M.P. 106 C.

EXAMPLE 10 4-H ydroxymethyl-I -2 -2"-Phenoxyeth0xyethyl-4-Phenylpiperidine Reduction, by the method detailed in Example 7, ofethyl-1-2-2"-phenoxyethoxyethyl 4 phenylpiperidine-4- car-boxyl ate gave4-hydroxymethyl-1-2'-2-phenoxyethoxyethyl-4-phenylpiperidine, M.P. 78 C.

EXAMPLE 11 l -2 -Benzylxyethyl-4-H ydroxym ethyl-4 -Phenyl p iperidineReduction, by the method detailed in Example 7, of ethyl1-2'-benzyloxyethyl-4-iphenylpiperidine-4-carboxylate gave1-2'-benzyloxyethyl-4-hydroxymethyl-4-phenylpiperidine, M.P. 82-84 C.

EXAMPLE 12 1 -2 -2 "-Hydr0xyethoxyethyl-4-Hydr0xymcthy l-4-Phenylpiperidine 4-hydroxymethyl-4-phenylpiperidine (10 parts) describedin Example 6, was refluxed in amyl alcohol parts) for 48 hours with2-chloroethyl-2'-hydroxyethyl ether (5 parts) over sodium carbonate (4parts). The mixture was allowed to cool and then filtered. The filtrateon distillation gave1-2'-2"-hydroxyethoxyethyl-4-hydroxymethyl-4-phenylpiperidine, B.P. 190C./ 0.2

What we claim is:

1. A compound selected from the group consisting of4-hydroxymethyl-4-phenyl-1 tetrahydrofurfuryloxyethylpiperidine,4-hydroxymethyl 4 phenyl-1-4'-ethoxybutylpiperidine, 4-hydroxymethyl 4phenyl-l-2-ethoxyethylpiperidine and4-1-hydroxypropyl-4-phenyl-1-2'-phenoxyethylpiperidine.

2. 4=hydroxymethyl-4+phenyl-1 tetrahydrofurfuryloxyethylpiperidine.

3. 4-hydroxymethyl 4 phenyl-l-4-ethoxybutylpiperidine.

4. 4-hydroxymethyl 4 phenyl-1-2'-ethoxyethylpiperidine.

5. 4-1'-hydroxypropyl-4-phenyl-1-2-phenoxyethylpiperidine.

References Cited in the file of this patent UNITED STATES PATENTS2,784,192 Schmidle et al Mar. 5, 1957 2,882,274 Jacob et a1. Apr. 14,1959 2,892,842 McElvain June 30, 1959 2,900,384 Rudner Aug. 18, 19592,927,111 Biel Mar. 1, 1960 OTHER REFERENCES Badger et al.: J oumal ofthe Chemical Society (1949), :page 1141.

Elpern: Journal of the American Chemical Society, volume 76, pages 281and 282 (1954).

Gaylord: Reduction with Complex Metal Hydrides (textbook), IntersciencePublishers Inc., New York (1956), pages 391393, 396 and 397.

Derwent: Belgian Report (Belgium patent abstract), volume 51B, page C24, Apr. 16, 1959.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF4-HYDROXYMETHYL-4-PENYL-1 - TETRAHYDROFURFURYLOXYETHYLPIPERIDINE,4-HYDROXYMETHYL - 4 - PHENYL-1-4''-ETHOXYBUTYLPIPERIDINE,4-HYDROXYMETHYL - 4 - PHENYL-1-2''ETHOXYETHYLPIPERDINE AND4-1''-HYDROXYPROPYL-4-PEHNYL-1-2''-PHENOXYETHYLPIPERDINE.